Ruxolitinib inhibits cyclosporine a (CSA) induced proliferation of squamous cell carcinoma (SCC): Implications for treating catastrophic SCC in organ transplant recipients (OTRs)

Immune-suppressed OTRs are prone to potentially deadly catastrophic SCC. Curative options that target cancer yet spare the allograft are unavailable. We have shown increased risk for catastrophic SCC in our OTR cohort via CSA-mediated induction of IL-22. Herein, we found that CSA drives SCC cell proliferation and tumor growth through IL-22 via JAK/STAT induction. We in turn inhibited that growth in vitro and in vivo via JAK 1/2 blockade with Ruxolitinib. We studied IL-22 and CSA induced proliferation in five SCC cell lines derived from patient tumors of varying metastatic potential; IL-22 receptor expression was markedly increased in the cell lines that metastasized, greatest proliferative response occurred in the least aggressive lines. IL-22 treated A431 SCC cells showed rapid STAT3 phosphorylation and increased STAT1, 3 and JAK1 expression on qPCR. We also found IL-22 and downstream JAK/STAT pathway related genes were highly expressed in CSA exposed transplant patients and in SCCs with perineural invasion. In nude mice engrafted with human SCC, IL-22 (4ug/d M-F, n=9) and CSA (20mg/kg d, n=9) increased tumor growth compared to vehicle (1.8 and 1.7-fold respectively, p<0.05) and upregulated IL-22 receptor, JAK1 and STAT 1/3 expression. Ruxolitinib treatment (2.5mg/d, n=8) reduced tumor volume by 44% (p<0.05) and reversed the accelerated tumor growth induced by CSA (53% volume reduction, p<0.05). IL-22 receptor expression was reduced in tumors exposed to Ruxolitinib. CSA and IL-22 hasten aggressive behavior in SCC. Targeting the IL-22 axis via selective JAK1 and STAT1/3 inhibition may reduce the progression of aggressive SCC in immunosuppressed OTRs without compromising tolerance of the transplanted organ.